Cyclic aminophosphonic acids

ABSTRACT

Cyclic aminophosphonic acids having the formula   wherein R is a member selected from the group consisting of hydrogen and alkyl having from 1 to 6 carbon atoms and n is an integer from 1 to 4; as well as their water-soluble salts. The cyclic aminophosphonic acids are excellent sequestering agents especially for alkaline earth metal ions. They are stabilizers for percompounds and are useful in the delaying of the setting times for gypsum. In addition, the compounds are useful in cosmetic preparations such as toothpastes and mouthwashes where they prevent formation of tartar and plaque and are useful in therapy in the treatment of diseases related to the abnormal deposition or dissolution of difficultly soluble calcium salts in the animal body.

United States Patent 11 1 I I 1111 3,925,456

Pliiger et al. Dec. 9, 1975 CYCLIC AMINOPHOSPHONIC ACIDS 1,002,3557/1957 Germany 260/502.5

[75] Inventors: Walter Ploger, Hilden Rhineland;

M f d schmidt ])unker, Primary Examiner-Joseph E. Evans D ld f;Christian Gloxhuber, Attorney, Agent, or Firm--l-1arnmond & Littell HaanRhineland, all of Germany [73] Assignee: Henkel & Cie GmbH, Dusseldorf,ABSTRACT Germany Cyclic aminophosphonic acids having the formula [22]Filed: Aug. 20, 1974 [21] Appl. No.: 498,996 0 R-N 1UOH [30] ForeignApplication Priority Data Aug. 27, 1973 Germany 2343195 /NHR o=c c o 52us. c1. 260/502.5; 106/3835; 106/395; ll

106/109; 210/58; 252/545; 252/DIG. 11; 260/429 J; 260/429.9; 424/54;424/209;

2 426/132 wherein R is a member selected from the groupcon- [51] Int.Cl. C07F 9/38 [58] E Id f Sea ch 260502 5 sisting of hydrogen and alkylhaving from 1 to 6 care o r hon atoms and n is an integer from 1 to 4;as wall as their water-soluble salts. The cyclic aminophosphonic [56]References Cited acids are excellent sequestering agents especially forUNITED STATES PATENTS alkaline earth metal ions. They are stabilizersfor per- 3,299,123 l/l967 Fitch et a1 260/502.5 compounds d are usefulin the delaying of the set- 3,322,863 5/1967 Rabourn et a1. 3,346,48710/1967 Irani et al. 3,363,032 l/l968 Fitch 3,404,178 10/1968 Roy3,565,949 2/1971 Cummins 3,595,957 7/1971 Muhler 3,617,576 11/1971 Kerst260/502-5 ting times for gypsum. In addition, the compounds are 260/5024P useful in cosmetic preparations such as toothpastes 2605025 andmouthwashes where they prevent formation of 260/502.4P d l d ful h h260/502'5 tartar an paque an are use in t erapy in t e 2605025 treatmentof diseases related to the abnormal deposi- 260/5025 tion or dissolutionof difficultly soluble calcium salts in 3,846,420 11/1974 Wollman et a1...260/502.5 the animalbody- FOREIGN PATENTS OR APPLICA'HONS 8 Claims, NoDrawings 995,462 6/1965 United Kingdom 260/502.5

CYCLIC AMINOPHOSPHONIC ACIDS THE PRIOR ART OBJECTS OF THE INVENTION Anobject of the present invention is the development of a cyclicaminophosphonic acid derivative selected from the group consisting of 1)compounds of formula NI-IR wherein R is a member selected from the groupconsist-' ing of hydrogen and alkyl having from I to 6 carbon atoms andn is an integer from 1 to 4, and (2) water-soluble salts thereof.

Another object of the present iiwention is the development of a processfor the production of the above cyclic aminophosphonic acids or theirwater-soluble salts.

Another object of the present invention is the development of a processfor the delaying or inhibiting of the precipitation of alkaline earthmetal ions from solution by the use of stoichiometric tosub-stoichiometric amounts of the above cyclic aminophosphonic acids ortheir water-soluble salts.

A further object of the present invention is the development of a methodfor delaying the setting time for gypsum which comprises adding to themixture of plaster materials and water a small amount of the abovecyclic aminophosphonic acids or their water-soluble salts.

Ayet further object of the present invention is the development of amethod for the treatment of diseases related to the abnormal depositionor dissolution of difficulty soluble calcium salts which comprisesadministering a safe but effective amount of at least one of the abovecyclic aminophosphonic acids or their water-soluble salts to thewarm-blooded animal.

These and other objects of the invention will become more apparent asthe description thereof proceeds.

DESCRIPTION OF THE INVENTION The above objects have been achieved by thedevelopment of new cyclic aminophosphonic acid derivative selected fromthe group consisting of l compounds of the formula wherein R is a memberselected from the group consisting of hydrogen and alkyl having from 1to 6 carbon atoms and n is an integer from 1 to 4, and (2) water-solublesalts thereof.

It has now been found that reactions of short-chained dicarboxylic aciddiamides or dinitriles with phosphorus trihalides or with phosphorustrihalides and phosphorous acid do not yield tetraphosphonic acids in asimilar manner as the corresponding reactions with monocarboxylic acidamides or nitriles give l-aminoalkanel ,l-diphosphonic acids. Rather itwas surprisingly noted that by reacting dicarboxylic acid derivatives ofthe formula X 2)" X wherein n is an integer from 1 to 4 and X representsthe radicals CN, CONH or CONHR' wherein R is an alkyl having I to 6carbon atoms, with phosphorus trihalides or phosphorus trihalides andphosphorus acid, with subsequent acid hydrolysis, the new cyclicaminophosphonic acids of Formula I are obtained.

wherein R is hydrogen or alkyl of l to 6 carbon atoms and n is aninteger of l to 4, or their water-soluble salts. The compounds ofFormula I are readily transformed into their water-soluble salts.

More particularly, the process of the present invention for theproduction of the cyclic aminophosphonic acids of Formula I consistsessentially of the steps of reacting a diacid compound of the formulawherein n is an integer from 1 to 4 and X is a member selected from thegroup consisting of CN, CONI-I and CONHR', where R is alkyl having 1 to6 carbon atoms, with at least the stoichiometric amount of a phosphorusreactant selected from the group consisting of a phosphorus trihalideand a mixture of a phosphorus trihalide and phosphorous acid, subjectingthe resulting reaction product to an acid hydrolysis by the action of anaqueous media selected from the group consisting of water and an aqueousmineral acid solution, and recovering said cyclic aminophosphonic acidderivative.

The above reaction can be so carried out, for example, that adicarboxylic acid diamide is first melted with phosphorous acid, andthat PCl is slowly added under stirring. The reaction product obtained,which is mostly viscous, is subsequently hydrolyzed by the addition ofwater. The addition of acids, such as mineral acids, is not necessary,because the reaction product itself is acid reacting.

However, when starting from dicarboxylic acid dinitrile, the latter canbe dissolved in an inert solvent, such as dioxane or chlorinatedhydrocarbons, and subsequently mixed with phosphorus trihalide. Thenphosphorous acid is added and, with the addition of water,

the reaction product is hydrolyzed. In the last mentioned method, thephosphorous acid can also be omitted, if desired. 1

In the above reactions, the phosphorus trihalides which can be used areparticularly phosphorus trichloride and phosphorus tribromide. Thelatter was found to be particularly suitable, if the nitriles areemployed as the starting material. I

The molar quantitative ratio of the dicarboxylic acid derivative to thephosphorus reactant is 1:2 to 1:6, preferably 1:4. The dicarboxylic acidamides .can also include those where one hydrogen atom is substituted inthe amino groups by an alkyl radical with 1 to 6, preferably 1 to 4carbon atoms.

Preferably the above-mentioned dicarboxylic acid derivatives of malonicacid, succinic acid and glutaric acid are used.

The new cyclic aminophosphonic acids are frequently obtained asmonohydrates and can be transformed by drying in the vacuum oven atabout 80C into the products without water of hydration. Thetitrimetrically determined molecular weights do not, at first, permitany differentiation between the monohydrate of the cyclic structuralFormula I above and the following aliphatic Formula II PO3H2 RNHCO-(CH2),,-CNHR u Po n where, again, n is an integer from 1 to 4 and Rhydrogen or alkyl with 1 to 6 carbon atoms. However, by determining thecontent of water of crystallization, it was ascertained that Formula Iis correct and that compounds of Formula II are formed at best only inan in significant amount.

The cyclic aminophosphonic acids can be easily transformed, if desired,intothe water-soluble salts, for example, by partial or completeneutralization with corresponding bases. The salts correspond to thefollowing Formula III where X denotes hydrogen, NI-L, or a metal cation,such as an alkali metal, but where at most two hydrogen atoms arepresent, R hydrogen or alkyl with 1 to 6, preferably 1 to 4 carbon atomsand n is an integer from 1 to 4.

The new cyclic aminophosphonic acids are excellent sequestering agentsfor polyvalent metal ions, particularly di and tri-valent metal ions.They are particularly suitable as sequestering agents for alkaline earthmetal ions, so that they can be used for many technical applications,such as in detergents and cleansers, as well as in water treatment. Theycan be employed in stoichiometric and substoichiometric amounts assequestering agents for alkaline earth metal ions. They also have astabilizing effect on percompounds.

They are also suitable as additives to delay the setting of gypsum andas ceramic slip liquifiers. For delaying the setting of gypsum, thepotassium, sodium or ammonium salts, in addition to the acids, can alsobe used. The corresponding lithium salts as well as zinc and magnesiumsalts are likewise suitable.

Furthermore, they can be used in mouth washes and tooth pastes in orderto-avoid the formation of tartar or plaque. The suitability of thecyclic aminophosphonic acids to be used according to the invention fortartar treatment and prophylaxis, results from their capacity ofinhibiting the formation of crystals in the precipitation of calciumapatite already in small amounts. Calcium apatite, which is precipitatedin the presence of the cyclic aminophosphonic acids, according to theinvention, is X-ray amorphous, in contrast to crystalline apatite, whichis usually formed without this addition.

The new cyclic aminophosphonic, acids and their water-soluble alkalimetal and ammonium salts are suitable as pharmacological activesubstances in pharmaceutical products. They have therapeutic and/orprophylactic effects in the treatment of a number of diseases, which arerelated to the abnormal deposition or dissolution of difficultly solublecalcium salts in the animal body. These diseases can be divided into twocategories:

l. Abnormal depositions of difficultly soluble calcium salts, mostlycalcium phosphate, cause bone malformations, pathological hardening oftissues and secretions in organs.

2. The abnormal dissolution of hard tissues causes losses of hard bonesubstance, which cannot be replaced or only by incompletely crystallizedtissue. This dissolution is frequently accompanied by pathologicallyhigh calcium and phosphate concentrations in the plasma.

These diseases include: osteoporosis, osteodystrophy, Pagets disease,myositis ossificans, Bechterews disease, cholelithiasis,nephrolithiasis, urinary calculus, hardening of the arteries(sclerosis), arthritis, bursitis, neuritis, tetany. i

In addition to the free cyclic aminophosphonic acids, theirpharmacologically harmless salts, such as the alkali metal salts, forexample, sodium or potassium or the ammonium salts or the substitutedammonium salts, such' as the lower alkanol ammonium salts like themono-, di-, 'or tri-ethanol ammonium salts can be used, for use inpharmaceutical preparations in the treatment of these diseases or fortheir prophylaxis. Both the partial salts, in which only a part of theacid protons are replaced by other cations, and full salts can be used,but partial salts, which react substantially neutral in aqueous solution(pl-I 5 to 9) are preferred. Mixtures of the above-mentioned salts canlikewise beused.

The dosage range of the cyclic aminophosphonic acids can be from 0.05 to500 mg per kg of the animal body weight. The preferred dose is l to 20mg per kg of body weight, and can be administered up to four timesdaily. The higher doses are necessary for oral application, due to thelimited resorption. Doses under 0.05 mg per kg of body weight havelittle effect on the path ological calcification or dissolution of bonesubstance. Doses above 500 mg/kg of body weight may have toxic sideeffects in the long run. The cyclic aminophosphonic acid derivatives canbe administered orally, subcutaneously or intraperitoneally in the formof tablets, pills, capsules or as injectable solutions. For animals thecyclic aminophosphonic acid derivatives can also be used as part ofthefeed or of feed additives. I

The following specific examples are illustrative of the practiceof theinvention without being limitative in any manner.

I EXAMPLE 1 2-Hydroxy-2-oxo-3-amino-3-phosphonyl 5-oxo 1 -aza-2-phospha-cyclopentane l ou a. 1.02 gm of malonic acid diamide (1.0 mol)and 164 gm of H 1 0 (2.0.mols) were'melted with exclusion of moisture at70C and mixed slowly under stirring with 175 ml of PCl (2.0 mols). Aviscous, yellow mass was formed which, after 4 hours, was hydrolyzedwith 1 liter of H 0. After filtration with activated carbon, the

6 a. 232 gm ofsuccinic acid diamide (2.0 mols) and 328gm of H PO (4.0mols) weremelted with exclusion of moisture at 70C and mixed slowlyunder stirring with 350 ml of PCl (4.0 mols). After 4 hours theresulting viscous, yellow mass was hydrolyzed with 2 liters of H 0. Thesolution was filtered with activated carbon and concentrated to 500 ml.On the'addition of 3 liters of ethanol and 3 liters of acetone, a whitecrystalline substance was precipitated. Yield of the crude2-hydroxy-3-oxo-3-amino-3-phosph0nyl-6-oxo- 1 -aza-2-phospha-cyclohexane was 180 gm A 35% of the the- The compound wasobtained as a monohydrate. The

filtrate was concentrated to 400 ml. On the addition of titrimetrgicanydetermined molecular weight was 260 4 liters of ethanol thereto, a whitecrystalline substance was precipitated. The 2-hydroxy-2-oxo-3-amino-3-phosphonyl-S-oxo-1-aza-2-phospha-cyclopentane was dried at 50C in avacuum drying oven. The crude yield was 142 gm 253% of the theory.

b. 33 gm of malodinitrile (0.5 mol) was dissolved in 200 ml of dioxaneand quickly mixed with 140 ml of PBr (1.5 mols). Then a solution of 41gm of H PO (0.5 mol) in 100 ml of dioxane was added slowly thereto understirring at 80C. The yellow solution was stirred for another 4 hours andthen hydrolyzed with 500 ml of H 0. After filtering with activatedcarbon, the solution was concentrated, the residue was taken up in 200ml of H 0 and a white crystalline. substance was precipitated therefromwith 2 liters of ethanol. Crude yield was 50 gm Q 38% of the theory.

The compound was isolated as a dihydrate of 2-hydroxy-2-oxo3-amino-3-phosphonyl-5-oxo-1-aza-2- phosphacyclopentane.The titrimetrically determined molecular weight was-266 (calc. 266.1).

' Analysis: Calculated: 13.54% C; 4.54% H; 10.53% N; 23.28% P. Found:13.48% C; 4.20% H; 9.97% N; 23.05% P.

After intensive drying, the anhydrous compound was obtained with amolecular weight, as determined titrimetrically, of 228 (calc. 230).

In the lR-spectrum the compound shows a 11 CO band at 1670 cm and a 8 NHband at 1615 cm. MP. 180C with decomposition.

EXAMPLEZ 2-Hydroxy-2-oxo-3-amino-3-phosphonyl-6-oxo- 1 -aza- 2-phospha-cyclohexane (calc. 262.1).

After drying at C in the vacuum drying oven, the anhydrous cycliccompound was obtained with a molecular weight of 244 (calc. 244).

Analysis: Calculated: 19.68% C; 4.13% H; 11.48% N; 25.38% P. Found:19.66% C; 4.07% H; 11.24% N; 25.32% PJ" The lR-spectrum of the substanceshows a very wide v CO band at 1640 cm which covers the 5 NH band. M.P.320C with decomposition.

EXAMPLE 3 1 -Methyl-2-hydroxy-2-oxo-3-methylamino-3-phosphonyl-6-oxo-1-aza-2-phospha-cyclohexane O OH P c11 N c OH \NHCH C CHEXAMPLE 4 l-Ethyl-2-hydroxy-2-oxo-3-ethylamino-3-phosphonyl- 6-oxol-aza-2-phospha-cyclohexane c H N C oH NH C2H5 O=C CH2 73.0 gm ofN,N-succinic acid biethylamide (0.424 mol) and 140 gm of H PO (1.7 mol)were melted in a 1 liter flask at 70C. Then, 149 ml of PC1 (1.7 mol)were added slowly while stirring. After 5 hours at 70C, the mass washydrolyzed with 250 ml of H and the resulting suspension was filteredwith activated carbon. The white phosphonic acid was precipitated fromthe filtrate with addition of 1 liter of ethanol and 1 liter of acetone.Crude yield 88.5 gm 2 69% of the theory.

After drying for 4 hours in the drying oven, the anhydrous cycliccompound 1-ethyl-2-hydroxy-2-oxo-3-ethylamino-3-phosphonyl-6-oxol-aza-2-phosphacyclohexane was obtained.The titrimetric determination of the molecular weight gave 299 (calc.300.2).

Analysis: Calculated: 32.01% C; 6.04% H; 9.33% N; 20.64% P. Found:31.60% C; 6.20% H; 9.21% N; 20.4% P.

The IR-spectrum of the compound shows a strong 11 CO band at 1605 cm.M.P. 240C with decomposition (sinters above 205C).

EXAMPLE 5 O OH C H N O 91.3 gm of N,N-succinic acid bisbutylamide (0.4mol) and 131 gm of H PO (1.6 mol) were melted at C and then 140.2 ml ofPCI;; (1.6 mol) were added slowly in drops. A viscous yellow mass isformed which is hydrolyzed, after another 6 hours at 70C with 300 ml ofH 0. After filtering the hot solution with activated carbon, the whitephosphonic acid 1-butyl-2- hydroxy-2-oxo-3-butylamino-3-phosphonyl-6-oxol aza-2-phospha-cyclohexane was precipitated from thefiltrate with ethanol and acetone. Yield 47 gm 2 31% of the theory.

After drying at 50C, the compound was obtained as a monohydrate. Themolecular weight was determined by titration at 377 (calc. 374).

Analysis: Calculated: 38.50% C; 7.54% H; 7.48% N; 16.55% P. Found:38.31% C; 7.37% H; 6.63% N; 15.91% P.

After drying at C in the vacuum drying oven, the

anhydrous compound was obtained. The molecular weight was determined at355 (calc. 356).

In the lR-spectrum, the substance showed a 11 CO band at 1605 cm.

EXAMPLE 6 2Hydroxy-2-oxo-3-amino-3-phospho nyl-7-oxo- 1 -aza-2-phospha-cycloheptane O OH P 0H P H N C OH l NH 0 C CH2 CH -CH a. 55 gmof glutaric acid diamine (0.42 mol) and gm of H PO (1.7 mol) were meltedat 70C and then mixed slowly with 149 ml of PCl (1.7 mol). After another4 hours at 80C, the mass was hydrolyzed with 400 ml of H 0 and the hotsolution was filtered with activated carbon. The white diphosphonic acidwas precipitated from the filtrate with ethanol and acetone.

Crude yield 40 gm Q 35% of the theory.

b. 94 gm of glutaric acid dinitrile (1.0 mol) were dissolved in 200 mlof dioxane and 278 ml of PBr (3.0 mols) were added slowly in drops at35C. Subsequently the mixture was heated to 70C and mixed slowly with asolution of 82 gm of H PO (1.0 mol) in 200 ml dioxane. After 16 hours at70C the mass was hydrolyzed with 250 ml of H 0. The mass was thenfiltered with activated carbon and the aqueous phase was separated fromthe filtrate. The white phosphonic acid was precipitated with ethanoland acetone. Crude yield 55 gm A 20% of the theory.

After brief drying at 50C, the compound 2-hydroxy-2-oxo-3-amino-3-phosphonyl-7-oxol -aza-2-phosphacycloheptane wasobtained as a monohydrate. The molecular weight was determined bytitrimetry as 276 (calc. 276).

EXAMPLE 7 l-Methyl-2-hydroxy-2-oxo-3-methylamino-3-phosphonyl-7-oxol-aza-2-phospha-cycloheptane OH- O P ll oH CH3-N NHCH3 CH -C H 63.2 gm ofN,N'-glutaric acid bismethylamide (0.4 mol) and 131 gm of H PO (1.6 mol)were melted at 70C and 140 ml of PCl (1.6 mol) were slowly added indrops. The resulting viscous yellow mass was held for another 6 hours at70C and then hydrolyzed with 250 ml of H 0. The solution was then boiledwith activated carbon and filtered. After cooling, the white phosphonicacid was precipitated with ethanol and acetone. Crude yield 57.5 gm 247% of the theory.

After drying at 50C, the 1-methyl-2-hydroxy-2-oxo-3-methylamino-3-phosphonyl-7-oxol -aza-2-phosphacycloheptane wasobtained as a monohydrate with a molecular weight of 305 (calc. 304).

Analysis: Calculated: 27.64% C; 5.96% H; 9.21% N; 20.37% P. Found:27.63% C; 5.83% H; 8.79% N; 20.25% P.

In the IR-spectrum of the compound the 11 CO band was at 1625 cm. Aftervigorous drying, the compound was obtained in anhydrous form with amolecular weight of 285 (calc. 286). MP. 274C with decomposition. 4

EXAMPLE 8 Sequestration of Calcium In the investigation of thesequestration of calcium, a modified Hampshire test was employed andworked as follows:

1 gm of the sequestering agent was dissolved in 50 ml of H 0,adjustedwith NaOH to a pH of l 1. 50 ml of a Ca1 solution (1470 mg ofCaCl -2I-I O/l) were mixed with 100 ml of a sodium carbonate solution(7.15 gm NaCO -lOH O/l.). Then the solution of the sequestering agentwas added in drops from a-burette until the calcium carbonateprecipitate was redissolved. The values formed have been reported inTable I. For the sake of simplicity, only the value for n and'thevarious substituents for R according to Formula I are indicated inthe left column of the Table.

TABLE I I RN i -OH 1' /NHR O=C C fi (CH P OH R alkyl having from 1 to 6carbon atoms n l to 4 Consumption of Compound sequestering mg CaCOSeques- Agent Solution tered per gm of n R (ml) Compound 1 H 2.6 1040 2H .6 1040 2 CH 3.0 840 2 C H 2.25 l 1 l0 3 H 3.1 810 3 CH 3.8 660Practically identical results were obtained if, instead of the acids,the corresponding sodium, potassium or ammonium salts were employed.

EXAMPLE 9 Threshold Effect The prevention of the precipitation of poorlysoluble calcium compounds by substoichiometric amounts of a sequesteringagent was determined at 60C and C as follows: i

25 ml of 80 dH (German hardness) water (corresponding to 800 mg CaO/l.)were mixed with a 10 ml of a solution of the sequestering agent(concentration: 300 mg/l. After dilution with distilled water to 70 ml,25 ml of a sodium carbonate solution containing 4 gm/l. were added andthe solution was brought to ml. After heating for 30 minutes at theindicated temperature, any precipitate formedwas separated. Thesequestering agent was removed from a measured amount of the clearfiltrate by means of an anion exchange resin. Then the content of thedissolved calcium in this sample was determined by complexometry(according to Schwarzenbach). The following Table II shows the portionof dissolved calcium in percent of the total amount of calcium used.

For the explanation of the data in the left column'of the Table, seeExample 8.

Practically identical results are obtained if, instead of the acids, thecorresponding sodium, potassium or ammonium salts were employed.

EXAMPLE 1O Delay of Setting in Gypsum Gypsum materialsin the form ofplaster, plaster-of Paris, or in mixture with aggregates, likelimestone, sand, perlite or cellulose, set relatively fast, so thatrapid processing must take place. A delay of the setting time can beachieved with the addition of the abovedescribed phosphonic acids, andthe processing of the gypsum materials can thus be considerablyfacilitated.

In the following tests, each of the various phosphonic acids of theinvention was added to the water before the gypsum was mixed. However,water-soluble salts of the phosphonic acids, particularly the lithium,sodium, potassium and ammonium salts can also be mixed instead with thegypsum or added shortly after the mixing of the gypsum material togetherwith the water. Specifically the following setting values were found andreported in Table 111, using in each test 20.0 gm of gypsum and 9 ml ofH 0. The setting time is the time interval in which the gypsum wasspreadable and easy to handle.

For the explanation of the data in the left column of Table III, seeExample 8.

TABLE III Amount Substance n R Setting Time (min.

Comparable results are obtained by using the corresponding magnesium andzinc salts.

EXAMPLE 1 1 Pharmaceutical Application TABLE IV LD Value Substance gm/kgb. Calcium phosphate dissolution in vitro Essential tests for theeffectiveness of the compounds in physiological systems are in vitrotests for the dissolving of freshly precipitated CaHPO as well aspreventing the precipitation of NH MgPO at a pH of 7.4. The CaHPO testwas carried out as follows.

By combining 25 ml of a phosphate solution (1.38 gm of NaH PO 'HO/liter, standardized to a pH of 7.4) and 25 ml of a calcium solution(1.47 gm of CaCl '2H O/- liter, standardized to a pH of 7.4), aprecipitate of CaH- P0 was produced. Thereafter, so much of a solutionof the sequestering agent (at a concentration of 10 mg/ml) was addedfrom a burette that a clear solution was obtained after standing for 1hour.

The results are compiled in the following Table V. The explanation ofthe date in the left column is to be found in Example 8.

TABLE v Dissolution of CaHPO4 Precipitation Consumption 0. Inhibition ofPrecipitation of NH MgPO in vitro Since the precipitation of NH MgPO isoccasionally the cause of the formation of urinary calculus, theinhibition of the precipitation of NH MgPO was also tested in aqueoussolutions at pH 7.4. The test was carried out as follows. I

A fixed amount of the phosphonic acid was weighed into a beaker anddissolved with 25 ml of a phosphate solution (13.799 gm of NaH PO 'HO/liter) as well as with 40 ml of distilled water, and standardized withNaOH to a pH of 7.4. After adding 25 m1 of a Mg and NH, solution (20.333gm of MgC '6H O and 5.349 gm of NH Cl/liter, standardized to a pH of7.4), the solution was brought up with distilled H O to ml. Then thesample was covered and evaluated after 72 hours for amount andappearance of the precipitate. Table VI gives the results of the test.The explanation of the data in the the left column is to be found inExample 8.

TABLE VI Inhibition of'NH MgPO, Precipitation Substance Amount n R (mg)Precipitation after 72 hours i Clear NH MgPO crystals,

normal crystal form 2 H 61 Few NH MgPO crystals' some cloudiness I 122No NH MgPO crystals, great cloudiness I 2 CH;, Very few NH MgPOcrystals,

no cloudiness 2175 No NH MgPQ, crystals, no

cloudiness 3 H 68.5 Fewer NH MgPO crystals, but

great cloudiness 3 CH;, 72 Few l' lH,,MgPO crystals, no

. cloudiness V 144 No NH.,MgPO crystals. no

cloudiness d. Apatite crystallization delay test in vitro supersaturatedsolutions of Ca and HPOf ions are relatively stable, but crystallizeafter the addition of an apatite nuclei according to the reaction.

5 Ca 3 HPO," H O Ca, Po,),oH+4 H* with the release of protons;Thereaction can,therefore, be readily observed by titration with a baseat a constantpH. M

400 ml of 0.0008 molar KH PO solution .were mixed with'45 ml of a 0.0l2'molar CaCl solution, and the clear solution was standardized with KOH toa pH of 7.4, after being broughtto a temperature of 35C. After 30minutesduring which time the pH did not change, a suspension of 100 mghydroxyl apatite in'50 ml of H 0 was added. The crystallization set inimmediately and was followedby -pH-Stat titration with 0.05 N KOH.

If a small amount (2 mg) of one of the cyclic aminophosphonic acids ofthe invention'was added to the so- TABLE VII Substance Delay ofcrystallization in after n R 4 Hours 8 Hours 2 CH: 84 76 3 H 96 96 e.Prevention of hardening of the aorta in rats The effectiveness of thecyclic aminophosphonic acids of the present invention in preventingabnormal calcium deposits in vivo in rats can be demonstrated asfollows.

This test was based on the observation that high doses of vitamin Dcause a considerable hardening of the aorta in rats. 30 Female ratsweighing 150 to 200 gm each were divided into three groups of 10 animalseach. They received during the test period a normal diet and tap waterad libitum. One group of 10 animals (control) received no furthertreatment. Another group of the animals received from the 3rd to the 7thday, 75,000 units of vitamin D daily through a stomach sound. The thirdgroup likewise received from the 3rd to the 7th day, 75,000 units ofvitamin D daily through a stomach sound and, in addition, likewiseorally, 10 mg per kg of one of the cyclic aminophosphonic acids from the1st to the 10th day. After 10 days the animals were sacrificed and theiraortas prepared and dried for 12 hours at 105C. After determination ofthe dry weight, the aortas were ashed; the residue was dissolved, andthe calcium was determined by flame photometry. The treatment withcyclic aminophosphonic acid reduced the vitamin D induced hardening ofthe aortas of rats considerably.

For the production of a pharmaceutical preparation in the form of acapsule, the known methods of preparation are followed to preparecapsules having a content per capsule as follows:

Cyclic aminophosphonic acid derivative of Formula I 100 mg Starch mgSodium laurylsulfate 1 mg For the preparation of a tablet, the followingrecipe was utilized per tablet:

Cyclic aminophosphonic acid derivative of Formula I 50 mg Lactose 100 mgStarch 35 mg Magnesium stearate 2 mg EXAMPLE l2 Cosmetic PreparationsThe following recipes are suitable as a basic formula for tooth pastes:

Parts by Weight (a) Glycerin 5 60.0 Water 13.5 Sodiumcarboxymethyl-cellulose 0.6 Sodium xero gel 20.0

Sodium laurylsulfate 2.0 Essential oils 1.0 sweetening agent 0.4 Cyclicaminophosphonic acid 2.5 (b) Glycerin 30.0 Water 18.5 Sodiumcarboxymethyl-cellulose 1.0 Aluminum hydroxide 44.0 Sodium laurylsulfate1.0 Pyrogenic silica 1.5 Essential oils 1.5 Sweetening agent 0.5 Cyclicaminophosphonic acid 2.0

Suitable as a basic formulation for mouthwashes is the following recipe:

Parts by Weight 19.5

Ethyl alcohol Any one of the compounds described in Examples 1 to 7 wereused as the cyclic aminophosphonic acid.

By regular use of the mouthwashes and/or toothpastes containing theabove-mentioned cyclic aminophosphonic acids, the formation of tartarcould be considerably reduced. The formation of hard compact plaque onthe teeth was to a great extent prevented.

The preceding specific embodiments are illustrative of the practice ofthe invention. It is to be understood, however, that other expedientsknown to those skilled in the art or discussed herein may be employedwithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A cyclic aminophosphonic acid derivative selected from the groupconsisting of 1) compounds of the formula wherein R is a member selectedfrom the group consisting of hydrogen and alkyl having from 1 to 6carbon atoms and n is an integer from 1 to 4, and (2) alkali metal orammonium salts thereof.

2. The cyclic aminophosphonic acid derivative of claim 1 wherein n is 1and R is hydrogen.

3. The cyclic aminophosphonic acid derivative of claim 1 wherein n is 2and R is hydrogen.

4. The cyclic aminophosphonic acid derivative of claim 1 wherein n is 2and R is methyl.

5. The cyclic aminophosphonic acid derivative of claim 1 wherein n is 2and R is ethyl.

6. The cyclic aminophosphonic acid derivative of claim 1 wherein n is 2and R is n-butyl.

7. The cyclic ammophosphomc acid derivative of l wh rem n mfthy claim 1wherein n is 3 and R is hydrogen.

8. The cyclic aminophosphonic acid derivative of 5

1. A CYCLIC AMINOPHOSPHONIC ACID DERIVATIVE SELECTED FROM THE GROUPCONSISTING OF (1) COMPOUNDS OF THE FORMULA
 2. The cyclic aminophosphonicacid derivative of claim 1 wherein n is 1 and R is hydrogen.
 3. Thecyclic aminophosphonic acid derivative of claim 1 wherein n is 2 and Ris hydrogen.
 4. The cyclic aminophosphonic acid derivative of claim 1wherein n is 2 and R is methyl.
 5. The cyclic aminophosphonic acidderivative of claim 1 wherein n is 2 and R is ethyl.
 6. The cyclicaminophosphonic acid derivative of claim 1 wherein n is 2 and R isn-butyl.
 7. The cyclic aminophosphonic acid derivative of claim 1wherein n is 3 and R is hydrogen.
 8. The cyclic aminophosphonic acidderivative of claim 1 wherein n is 3 and R is methyl.